tbuckley/cabot-search huggingface dataset:
INNV-41. SUCCESSFUL TREATMENT OF EXTREMELY RARE CASE OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOPLASMACYTIC LYMPHOMA WITH BENDAMUSTINE-RITUXIMAB REGIMEN: A CASE REPORT
Authors: Kaitlyn Sy, Sunveer Mogla, Jaswinder Singh, Eston Shhwartz, Sakshi Dixit, Amandeep Kalra
Journal: Neuro-Oncology (2023)

Abstract Lymphoplasmacytic lymphoma (LPL) is an uncommon low-grade non-Hodgkin B-cell lymphoma, with an annual incidence rate of 3 to 4 cases per million people. Primary central nervous system lymphoplasmacytic lymphoma (PCNSLPL) is even rarer, with fewer than 30 cases documented in the literature so far, to our knowledge. We report a case of a 40-year-old Caucasian male who presented with headaches and mild short-term memory problems. CT was suggestive of a right parietal mass. MRI revealed a right parietal homogeneously contrast-enhancing mass with T2 and flair changes extending to the right lateral ventricle, suggestive of vasogenic edema. An open biopsy was performed, and immunohistochemical analysis of the sample indicated lymphoplasmacytic lymphoma. PET scan was negative for hypermetabolic lesions. Bone marrow biopsy, serum protein electrophoresis, urine protein electrophoresis, and CSF analysis were unremarkable. A diagnosis of primary central nervous system lymphoplasmacytic lymphoma (PCNSLPL) was given after comprehensive workup. Treatment with 10 cycles of bendamustine and rituximab (BR regimen) resulted in a good response. The patient has been clinically stable and improving for over a year. Radiologically, there has been interval shrinkage of the right parietal mass and follow-up scans continue to be stable. The plan is to continue maintenance rituximab for 2 years. Although extremely rare, PCNSLPL should be considered in differential diagnoses of hematolymphoid tumors of the CNS and bendamustine with rituximab as induction treatment followed by maintenance rituximab might be considered.
MODL-47. A NEW MOUSE MODEL OF IDH MUTATED GLIOMAS IDENTIFIES TUMOR CELLS OF ORIGIN AND DETERMINANTS OF SENSITIVITY TO IDH INHIBITORS
Authors: Eric Laugesen, Ruxiao Tian, Annette Wu, Samah El Ghamrasni, Adrian Levine, Zoya Aamir, Liana Figueiredo Nobre, Kevin Petrecca, Samuel McBrayer, Mario Suva, Cynthia Hawkins, Uri Tabori, Daniel Schramek, Tak Mak, Jerome Fortin
Journal: Neuro-Oncology (2023)

Abstract Driver mutations in IDH1 and IDH2 characterize a substantial proportion of diffuse gliomas. These tumors are typically of lower grade at diagnosis, but many eventually transform to more aggressive disease. Furthermore, there is a lack of effective curative treatments. Mutated IDH molecules acquire neomorphic enzymatic activity, favoring the synthesis of D-2-hydroxyglutarate (D-2-HG). Accumulation of this metabolite perturbs many cellular functions and drives gliomagenesis through incompletely understood mechanisms. IDH mutations are early events in gliomagenesis, but the identity of the initiating cell type has been debated. Here, using genetically engineered mice, we found that combining Idh1R132H and Trp53 loss in oligodendrocyte progenitors leads to fully penetrant development of diffuse gliomas. The tumors recapitulate the cardinal features of the corresponding human disease. While heterogeneous, the mouse Idh1R132H and Idh1WT tumors show distinct patterns of transcriptional alterations and oncogenic copy number variants. Mutant IDH itself is an attractive drug target, as it is clonally expressed and usually retained during tumor evolution, even though its relevance for disease progression has been questioned. Nevertheless, recent clinical trials have demonstrated clear, but variable, anti-tumor effects of mutant IDH inhibitors in patients. To better understand the mechanistic basis for heterogeneous responses to mutant IDH inhibition, we performed CRISPR/Cas9 functional genomic screens in cell lines derived from the mouse Idh1R132H;Trp53MUT tumors. These revealed interactions between the mutant IDH inhibitor vorasidenib and molecules related to astrocytic differentiation, Notch signaling, and cell growth and metabolism. The translational relevance of these findings was supported by molecular data from human tumors, patients treated with IDH inhibitors, and human-derived cell models. Overall, these studies nominate oligodendrocyte progenitors as candidate cells of origin for IDH mutated gliomas, and point to strategies that may enhance the efficacy of IDH inhibitors.
TMIC-45. SEX DIFFERENCES IN <i>YAP1</i>-CD276 EXPRESSION AND FUNCTION IN MEDULLOBLASTOMA IMMUNE EVASION
Authors: Nourhan Abdelfattah, Sivaraman Natarajan, Jose Madonado, Hannah Borland, Rachael McMinimy, Shu-hsia Chen, Fernando Camargo, James Olson, Joshy George, Kyuson Yun
Journal: Neuro-Oncology (2023)

Abstract Sex differences in human diseases are well established; however, little is known about the molecules that link oncogenic events and sex as a biological variable in tumorigenesis and treatment response. Here, we report that Yap1 has a sex-specific role in SHH medulloblastoma (MB) progression and immune suppression. Through integrated genomic, transcriptomic, proteomic, and in vivo transcriptional target analyses, we show that Yap1 concurrently promotes stemness and blocks differentiation of cancer stem cells through at least two distinct but complementary molecular mechanisms. In parallel, Yap1 also promotes immune suppressive tumor microenvironment by directly regulating CD276, Csf1, Igf1, and Igfbp3 transcription and modulating the IL6-JAK-STAT3, TNFR1, TGF-β, and CCL5 immune pathways. Notably, while Yap1 function is critical for promoting stemness in male and female MB cells, Yap1 plays a more dominant role in promoting immune suppression and Th2 polarization in male MBs. Furthermore, we discovered that a YAP1-target gene, CD276, expression level is higher in female MBs in both mice and humans, demonstrating for the first-time sex differences in expression levels of an immune checkpoint molecule in MB. Functionally, anti-CD276 treatment is more effective in reversing T cell suppression from male MB cells compared to female MB cells, and CD276 expression level stratifies male but not female MB patient survival. Supporting the clinical relevance of our findings, we show that the sex difference in Yap1 function is evolutionarily conserved across multiple tumor types: YAP1 target gene signature predicts poor survival in males but not females in MB, glioblastoma, low-grade glioma, mesothelioma, and hepatocellular carcinoma. In summary, we provide the first evidence of sex-biased expression and function of YAP1 and CD276 in mouse and human cancers and identified the YAP1-CD276 axis as a key contributor to sex differences in immune checkpoint response.
TMIC-26. TAMS AND HYPOXIA ENHANCE GLIOBLASTOMA STEM-LIKE CELL ENRICHMENT AND MAY IMPACT RADIORESISTANCE
Authors: Victor Karwacinski, Tatiana Carneiro-Lobo, Cheryl Olson, Mayerli Constante, Pinar Mesci, Daniel Brat, Alysson Muotri
Journal: Neuro-Oncology (2023)

Abstract The dismal survival rates of glioblastoma (GBM) patients are due, at least in part, to therapeutic resistance of GBM stem-like cells (GSCs) and their ability to repopulate recurrent tumors. Our goal was to determine if tumor-associated macrophages (TAMs) or hypoxia enhance the enrichment of GSCs in a manner that could impact radioresistance. First, we established GBM-brain cortical organoids (GBM-BCOs) to model human GBM. We co-cultured GFP-labeled GBM neurospheres with BCOs for 14 days and observed a tumor take rate of 100%. Next, we evaluated whether hypoxia enhanced TAM migration into GBM-BCOs by incorporating THP-1 cells into GFP-GBM-BCOs and incubating them for 24 h under normoxic or hypoxic conditions. We found that hypoxia significantly increased THP-1 cell influx into GBM-BCOs. Further, we investigated whether TAMs influenced the enrichment of GSCs in GBM neurospheres and in GBM-BCOs. We found that co-culture of THP-1 cells with either GBM neurospheres or with GBM-BCOs enhanced the CD133+ population after 72 h hypoxia, correlating with our IF studies of human GBM samples that show increased CD133+ and IBA1+ cells in hypoxic peri-necrotic zones compared to non-necrotic regions. Next, we established Fluorescent Ubiquitination-based Cell Cycle Indicator (FUCCI), an advanced methodology for monitoring cell cycle phases for investigating the role of hypoxia and radiation on GBM. Flow cytometry analysis of patient-derived GBM cells revealed that the fraction of G1 cells decreased and the fraction of G2/M cells increased 24 h after 3 Gy radiation compared to non-irradiated cells in normoxia. In contrast, GBM cells exposed to hypoxia do not show such cell cycle shifts after radiation and have an enriched population of cells in G0 in both radiated and non-irradiated cells. Our results indicate that hypoxia and TAMs play critical roles in GSC enrichment and may impact radioresistance.
TMIC-42. ACROLEIN PRODUCED BY GLIOMA CELLS UNDER HYPOXIA INHIBITS NEUTROPHIL AKT ACTIVITY AND SUPPRESSES ANTI-TUMORAL ACTIVITIES
Authors: Zhen-Jie Tong, Hong-Chieh Tsai, Tsong-Long Hwang, Hsiang-Tsui Wang
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM), WHO grade 4 glioma, is the most malignant primary brain tumor. The median overall survival of GBM ranges from 12 to 16 months. The tumor microenvironment of GBM is characterized by tissue hypoxia and infiltration of immunosuppressive cells. Neutrophils have been reported to shift from an anti-inflammatory phenotype to a pro-tumoral role (N2 phenotype) during glioma progression. However, the mechanism of this transformation remains unclear. Acrolein (Acr) is a highly-reactive α,β-unsaturated aldehyde produced under hypoxic conditions via lipid peroxidation, resulting in cellular impairment through DNA or protein conjugation. In this study, we found that acrolein produced by U87MG cells under hypoxic conditions suppresses neutrophil superoxide generation, inhibits neutrophil tumor-suppressive activities, and induces N2 marker arginase 1 (Arg-1) expression. Scavenging acrolein with dimercaprol reverses these effects. Further investigation revealed that acrolein inhibits AKT enzymatic activity by forming Acr-AKT conjugates at Cys 310. In a syngeneic subcutaneous mice glioma model, dimercaprol treatment is associated with decreased tumor size, reduced acrolein conjugate expression in the tumor tissue, and restored neutrophil superoxide generation. In addition, we also found that the higher acrolein-DNA adduct expression in tumor tissues is associated with a poor prognosis of glioma patients, and the evaluated acrolein-protein conjugates in the serum of glioma patients are correlated to the functional impairment of neutrophils. These results suggest acrolein polarizes the neutrophils toward the N2 phenotype and contributes to the immunosuppressive microenvironment and glioma progression. Acrolein scavenging may be a novel strategy for glioma treatment.
PATH-43. INFRATENTORIAL IDH-MUTANT ASTROCYTOMAS REQUIRE HIGH INDEX OF SUSPICION FOR ACCURATE DIAGNOSIS
Authors: David Ormond, Samuel Guzman, Douglas Ney, B K DeMasters
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Banan et al (PMID 2776277) recently identified infratentorial IDH-mutant astrocytomas (Inf-IDHmt) as a distinct subtype in which 80% have non-canonical mutations, precluding the use of IDH1 R132H immunohistochemistry (IHC) for diagnosis. They note “molecular testing is critical for detection of these tumors”. Only 47% have ATRX loss by IHC and only 56% have MGMT promotor methylation. Thus, it is critical that neurosurgeons take this into account during surgical planning due to the requirement for adequate tissue sample volume necessary for diagnosis. We review these diagnostic challenges in our recent single institution experience with these tumors. METHODS Database text word searches were conducted for the years 2007-2023 to generate cases, coupled with chart review. RESULTS 7 cases were identified: 3 male and 4 female, ages 27-44. All cases were small stereotactic biopsies. The histological diagnosis was made exceptionally challenging by paucity of tumor cells (especially in grade 2), coupled with the fact that 5 of 7 had non-canonical IDH-mutation and 5 of 7 showed ATRX retention by IHC, necessitating a very high index of suspicion on the part of the pathologist to send for next-generation sequencing (NGS). Due to the rare co-expression of IDH and histone mutations in this subtype, 6 of 7 had H3 K27M IHC conducted; all were negative. Due to small tissue volumes, MGMT promotor methylation testing could only be conducted on 3 of 7 cases; testing was uninformative on these 3. CONCLUSION Preoperative high index of suspicion is required to obtain maximal safe biopsy volumes of tissue for molecular and MGMT methylation testing, which should be conducted on virtually all brainstem and cerebellar biopsies.
CNSC-12. PATHOLOGY SPECIFIC, PHARMACOLOGICALLY REVERSIBLE LOSS OF NEURONAL FUNCTION IN HUMAN GLIOMAS
Authors: Gray Umbach, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2023)

Abstract Prior evidence has demonstrated that neuronal activity is preserved within glioma-infiltrated cortex and maintains the ability to engage in task specific computations albeit with information loss. These findings support a potential therapeutic target to rescue cognitive impairments seen in nearly all afflicted patients if neuronal activity can be recovered. We developed an in vivo human behavioral and electrophysiological model to assess neuronal population tuning responses within primary sensory cortex including the decodability of stimuli and task-related changes in population spiking in a cohort of 14 human patients undergoing awake resection. We placed high-density electrode arrays to record human local field potentials from gliomas projecting to the cortical surface. We next designed a static sensory detection threshold task, stimulating with a tachometer at two different face and hand sites totaling 11,200 trials while recording from macroelectrode cortical contacts over both tumor-infiltrated (50 electrodes) and normal appearing cortex (52 electrodes). In tumor-infiltrated cortex, the ability to decode the site of stimulation using the oscillatory power in both theta (4-8 Hz) and gamma (32-70 Hz) bands was reduced compared to normal appearing cortex. However, tumor-infiltrated cortex-maintained selectivity between hand and face stimulation. Targeted next-generation tumor sequencing uncovered novel molecular targets of glioma-neuronal integration. The degree of loss of selectivity correlated with WHO grade and pathology. WHO grade 4 tumors and oligodendrogliomas compared to astrocytomas demonstrating greater loss of selectivity. Gabaergic agonist has been postulated to restore neuronal selectivity in aging and neurodegenerative disease. Therefore, we next computed GABA agonist dose (estimated by time off Propofol and beginning of behavioral testing). Higher concentrations of GABA agonist correlated with improved theta band selectivity and decodability. These results suggest that loss of neuronal computations in glioma-infiltrated cortex is caused by loss of neuronal selectivity and is both tumor selective and pharmacologically reversible.
TMIC-47. INHIBITION OF MIR-146A-5P DECREASES PROGRESSION OF MELANOMA BRAIN METASTASIS VIA NOTCH PATHWAY DYSREGULATION IN ASTROCYTES
Authors: Emma Rigg, Jiwei Wang, Zhiwei Xue, Taral Lunavat, Guowei Liu, Tuyen Hoang, Himalaya Parajuli, Mingzhi Han, Rolf Bjerkvig, Petr Nazarov, Nathalie Nicot, Stephanie Kreis, Christiane Margue, Miléne Tetsi Nomigni, Jochen Utikal, Hrvoje Miletic, Lars Ystaas, Terje Sundstrøm, Xingang Li, Frits Thorsen
Journal: Neuro-Oncology (2023)

Abstract Melanoma has a high propensity for brain metastasis, occurring in 40% of late-stage patients. The progression of secondary tumors in the brain depends on the support of the surrounding microenvironment, emphasizing the importance of modulating neighboring cells for successful metastasis. Tumor-derived extracellular vesicles (EVs) play a crucial role in creating a pre-metastatic niche for tumor growth by transferring proteins, RNA, and DNA. This study aims to explore the involvement of melanoma brain metastasis (MBM)-derived EVs in MBM development and identify a target miRNA for potential therapeutic intervention. In an in vivo metastatic model, MBM-EV pre-treated mice exhibited significantly increased MBM tumor burden compared to non-primed mice. In vitro co-cultures of MBM-derived EVs with astrocytes led to astrocyte activation characterized by enhanced proliferation, invasion, cytokine production, and upregulation of GFAP. Microarray analysis revealed significant upregulation of miR-146a-5p in MBM-EVs compared to healthy astrocyte and melanocyte EVs. In situ hybridization of clinical MBM samples showed significantly elevated miR-146a-5p expression compared to healthy brain controls. Sequencing of NHA after co-culture with miR-146a-5p mimic revealed NUMB, a Notch signaling pathway inhibitor, as a miR-146a-5p target. Expression levels of Numb and other downstream Notch proteins were significantly altered in NHA in the presence of MBM-derived EVs and miR-146a. Deserpidine was identified as a potential inhibitor of miR-146a-5p through a drug docking study, and qPCR analysis confirmed reduced miR-146a-5p expression in deserpidine-treated MBM cells and EVs in vitro. In an MBM in vivo model, deserpidine-treated mice exhibited significantly increased survival, reduced tumor burden, and decreased astrocyte activation in both tumor and non-tumor brain tissues. In conclusion, EVs are important regulators of MBM and establish tumor-supporting reactive astrocytes by delivery of miR-146a. Elevated miR-146a levels in patients suggests a potential clinical intervention, and our results indicate deserpidine as a promising candidate for adjuvant therapy.
TMET-19. TARGETING AMINO ACID METABOLIC VULNERABILITIES IN IDH-MUTANT AND IDH-WILDTYPE GLIOMAS
Authors: Shigeo Ohba, Takao Teranishi, Akiyoshi Hirayama, Keisuke Hitachi, Hisateru Yamaguchi, Manabu Natsumeda, Kensuke Tateishi, Russell Pieper, Yuichi Hirose
Journal: Neuro-Oncology (2023)

Abstract IDH-wildtype and IDH-mutant glioma have different genetical and metabolic background although their histological appearances are similar. The aim of the study is to reveal the difference in metabolites between IDH-wildtype glioma and IDH-mutant glioma, and to find the effective treatment according to the status of IDH in gliomas. Two artificial cell lines made from human astrocyte were used: NHAE6E7hTERTRas (IDH-wildtype) and NHAE6E7hTERTIDHmut (IDH-mutant). Capillary electrophoresis- and ion chromatography–coupled mass spectrometry revealed that the amount of asparagine was lower in NHAE6E7hTERTRas cells compared with NHAE6E7hTERTIDHmut cells. L-asparaginase, which converts asparagine into aspartate, was more effective in former cells than latter cells. L-asparaginase induced autophagy and inhibition of autophagy by 3-MA suppressed L-asparaginase-induced antitumor effect, which meant that the antitumor effect was at least partially due to the L-asparaginase-induced autophagy. Metabolic assay also showed the lower amount of glutamine, glutamate and 2-oxoglutarate in NHAE6E7hTERTIDHmut cells than NHAE6E7hTERTRas cells. Pharmacological or genetical inhibition of GLUD1 which converts glutamate to 2-oxoglutarate, suppressed proliferation of the cells by inducing ROS and apoptosis in NHAE6E7hTERTIDHmut cells. ROS inhibitor, NAC suppressed GLUD1 inhibitor-induced ROS, apoptosis, and cytotoxicity in NHAE6E7hTERTIDHmut cells, revealing that cytotoxicity by GLUD1 inhibitor was at least partially due to the inhibitor-induced ROS. Mutant IDH1 overexpressed glioma cell line showed similar sensitivity to GLUD1 inhibitor to NHAE6E7hTERTIDHmut, which suggested that the difference of sensitivity to GLUD1 inhibitor was due to the status of mutant IDH. In addition, GLUD1 inhibitor suppressed the growth of xenografted glioma cells with overexpressed mutant IDH1. In conclusion, L-asparaginase and Glud1 inhibitor will be new therapeutic option for IDH-wildtype glioma and IDH-mutant glioma, respectively.
SURG-21. THE PROGNOSTIC ROLE OF RE-RESECTION FOR RECURRENT GLIOBLASTOMA: A REPORT OF THE RANO <i>RESECT</i> GROUP USING A NOVEL CLASSIFICATION FOR EXTENT OF RESECTION
Authors: Philipp Karschnia, Antonio Dono, Jacob Young, Stephanie T Juenger, Levin Häni, Nico Teske, Tommaso Sciortino, Christine Y Mau, Francesco Bruno, Luis Nunez, Ramin Morshed, Alexander F Haddad, Michael Weller, Martin van den Bent, Juergen Beck, Shawn Hervey-Jumper, Annette Molinaro, Nitin Tandon, Roberta Rudà, Michael A Vogelbaum, Lorenzo Bello, Oliver Schnell, Stefan J Grau, Susan Chang, Mitchel Berger, Yoshua Esquenazi, Joerg-Christian Tonn
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The role of re-resection in recurrent glioblastoma remains controversial since leaving certain tumor volumes deliberately behind cannot be ethically justified. We aimed to (I) analyze the prognostic value of re-resection using the novel RANO resect classification for quantification of residual tumor, and (II) explore factors that favorably consolidate the effects of re-resection on outcome. METHODS The RANO resect group retrospectively accumulated a global, eight-center cohort of patients with first recurrence from a previously resected glioblastoma. The associations of re-resection and clinical factors with outcome were analyzed. Propensity score-matched analyses were constructed to mimic randomized clinical trials comparing different residual tumor volumes. RESULTS We analyzed 681 patients with first recurrence of IDH-wildtype glioblastoma, including 310 patients who underwent re-resection at first recurrence. The use of re-resection was associated with prolonged survival also when stratifying for molecular and clinical confounders (HR:0.65, CI:0.5-0.8; p = 0.001). Smaller post-operative contrast-enhancing (CE) tumor volumes were favorably associated with outcome of re-resected patients (HR per cm3:1.04, CI:1.0-1.1; p = 0.009), and ≤ 1 cm3 residual CE tumor translated into improved survival compared to non-surgical management. Accordingly, ‘maximal resection’ (class 2) had superior survival compared to ‘submaximal resection’ (class 3) (mOS after recurrence: 12 vs. 9 months; p = 0.003). Adjuvant chemotherapy further augmented the beneficial effects of lower residual CE tumor. Conversely, ‘supramaximal resection’ of non-CE tumor (class 1) was not associated with prolonged survival but frequently accompanied by post-operative deficits, hampering further treatment. The prognostic role of residual CE tumor was confirmed in propensity score analyses. CONCLUSION Residual CE tumor is highly prognostic in recurrent glioblastoma and the RANO resect classification serves to stratify patients accordingly. Chemotherapy may favorably contribute to the prognostic associations of re-resection. When pursuing re-resection of non-CE tumor, intraoperative mapping strategies to minimize the risk of post-operative deficits are recommended.